ABT-199 rebounds in advanced CLL after tackling tumor lysis syndrome

MILAN – The investigational Bcl-2 inhibitor ABT-199 continues to impress with substantial activity as single-agent or combination therapy in relapsed or refractory chronic lymphocytic leukemia, following dose-scheduling modifications to address the risk of tumor lysis syndrome.

ABT-199 monotherapy

Updated data from all 105 CLL patients in the phase I trial show the overall response rate remains high at 77%, with 23% of patients achieving complete remission.

Seven of 11 complete responders assessed had no detectable minimal residual disease, Dr. John F. Seymour said at the annual congress of the European Hematology Association.

Overall response rates were sustained in the 75%-80% range for high-risk patients with deletion 17p, fludarabine-refractory, or immunoglobulin heavy-chain variable (IGHV)-unmutated CLL; and complete response rates in these subgroups also did not differ from the overall group at 22% to 29%.

Prior results from the first-in-human trial dazzled the leukemia community, but tumor lysis syndrome (TLS) complications, including two fatal events, temporarily halted ABT-199 clinical trials and gave the advantage to its closest competitor, the recently approved and more tolerable CLL drug ibrutinib (Imbruvica).

Use of a modified, ramp-up dosing scheme and aggressive TLS prophylaxis appear to have ameliorated the risk of TLS, with no further clinically significant or grade 3 or 4 events reported in the 49 patients treated with this schema, said Dr. Seymour, director of hematology and cancer medicine at the Peter MacCallum Cancer Centre, East Melbourne, Australia.

Rather than using a 3-week schedule and 50-mg starting dose, the safety expansion cohort received once-daily oral ABT-199 beginning at 20 mg, with weekly adjustments to 50 mg, 100 mg, 200 mg, and 400 mg over 5 weeks.

The 400-mg dose has been identified as the phase II dose, with 59% of patients free of progression at 18 months and beyond on this dose, he said.

As of April 2014, 37 of the 105 patients discontinued treatment, 22 due to progressive disease and 12 for adverse events; in addition, two proceeded to allogeneic hematopoietic cell transplantation, and one needed Coumadin, which is not permitted on protocol.

The median duration of response has not yet been reached for patients treated at doses of 400 mg or above, he said.

The most common treatment-emergent adverse events of any grade were diarrhea (40% of patients), neutropenia (36%), and nausea (35%).

Neutropenia was the only grade 3/4 event occurring in more than 10% of patients (33%), followed by anemia in 10%.

Combination ABT-199

Of substantial interest to many was a second phase Ib study presented in the same session, evaluating the role of ABT-199 with the anti-CD20 antibody rituximab (Rituxan) in relapsed or refractory CLL.

After a median time on study of just 7.5 months, the overall response rate was 84% among 25 evaluable patients, including 9 complete responses (36%) and 12 partial responses (48%), said Dr. Andrew W. Roberts, with the Royal Melbourne (Australia) Hospital and Walter and Eliza Hall Institute of Medical Research.

Six of eight complete responders tested were negative for minimal residual disease by flow cytometry.

Preliminary pharmacokinetic results suggest no apparent effect of rituximab on ABT-199 exposure, he said.

Three patients discontinued ABT-199 after achieving a complete remission, including one with fludarabine-refractory disease, and all remain in complete remission at 8.6, 8.8, and 11.6 months after cessation.

Dose modifications were also made in this study following a fatal TLS event in December 2012 after a first dose of ABT-199 at 50 mg. Under the modified step-up dosing, ABT-199 was started at 20 mg, escalating up to 600 mg daily over 5 weeks, with rituximab 375 mg/m² added on day 1 of week 5 and rituximab 500 mg/m² added on day 1 of months 2-6.

The combination was well tolerated, and no new safety concerns were identified, Dr. Roberts said. The most common grade 3/4 adverse events among 45 patients evaluable for safety were neutropenia in 47%, anemia in 16%, thrombocytopenia in 13%, and febrile neutropenia in 7%. Grade 3/4 neutropenia was more common at 600 mg, with the 400-mg dose selected for the ongoing safety expansion cohort. Two serious TLS events occurred, but both were prior to schedule modifications, he said.

One patient in the combination study and 13 in the monotherapy study received treatment for small lymphocytic lymphoma. Response rates and tolerability were similar between CLL and SLL patients in the monotherapy study, Dr. Roberts said in an interview.

During a press briefing at the meeting, Dr. Seymour said ABT-199 potentially could be combined with ibrutinib and that the combination was very potent in laboratory tests in both CLL and some forms of mantle cell lymphoma. Negotiations with the various companies involved are intricate, but there is agreement and commitment "to begin clinical trials of the combination later this year," he added.

ABT-199 is currently being evaluated in a phase II trial as monotherapy in deletion 17p relapsed CLL, as combination therapy with rituximab versus bendamustine plus rituximab in a phase III trial in relapsed/refractory CLL, and in combination trials with bendamustine/rituximab and obinutuzumab in relapsed/refractory CLL.

AbbVie and Genentech sponsored the trials. Dr. Seymour is a consultant and adviser for AbbVie, Genentech, and Roche. Dr. Roberts reported research funding from AbbVie and Genentech and milestone payments to his institution related to ABT-199.

pwendling@frontlinemedcom.com

MILAN – The investigational Bcl-2 inhibitor ABT-199 continues to impress with substantial activity as single-agent or combination therapy in relapsed or refractory chronic lymphocytic leukemia, following dose-scheduling modifications to address the risk of tumor lysis syndrome.

ABT-199 monotherapy

Updated data from all 105 CLL patients in the phase I trial show the overall response rate remains high at 77%, with 23% of patients achieving complete remission.

Seven of 11 complete responders assessed had no detectable minimal residual disease, Dr. John F. Seymour said at the annual congress of the European Hematology Association.

Overall response rates were sustained in the 75%-80% range for high-risk patients with deletion 17p, fludarabine-refractory, or immunoglobulin heavy-chain variable (IGHV)-unmutated CLL; and complete response rates in these subgroups also did not differ from the overall group at 22% to 29%.

Prior results from the first-in-human trial dazzled the leukemia community, but tumor lysis syndrome (TLS) complications, including two fatal events, temporarily halted ABT-199 clinical trials and gave the advantage to its closest competitor, the recently approved and more tolerable CLL drug ibrutinib (Imbruvica).

Use of a modified, ramp-up dosing scheme and aggressive TLS prophylaxis appear to have ameliorated the risk of TLS, with no further clinically significant or grade 3 or 4 events reported in the 49 patients treated with this schema, said Dr. Seymour, director of hematology and cancer medicine at the Peter MacCallum Cancer Centre, East Melbourne, Australia.

Rather than using a 3-week schedule and 50-mg starting dose, the safety expansion cohort received once-daily oral ABT-199 beginning at 20 mg, with weekly adjustments to 50 mg, 100 mg, 200 mg, and 400 mg over 5 weeks.

The 400-mg dose has been identified as the phase II dose, with 59% of patients free of progression at 18 months and beyond on this dose, he said.

As of April 2014, 37 of the 105 patients discontinued treatment, 22 due to progressive disease and 12 for adverse events; in addition, two proceeded to allogeneic hematopoietic cell transplantation, and one needed Coumadin, which is not permitted on protocol.

The median duration of response has not yet been reached for patients treated at doses of 400 mg or above, he said.

The most common treatment-emergent adverse events of any grade were diarrhea (40% of patients), neutropenia (36%), and nausea (35%).

Neutropenia was the only grade 3/4 event occurring in more than 10% of patients (33%), followed by anemia in 10%.

Combination ABT-199

Of substantial interest to many was a second phase Ib study presented in the same session, evaluating the role of ABT-199 with the anti-CD20 antibody rituximab (Rituxan) in relapsed or refractory CLL.

After a median time on study of just 7.5 months, the overall response rate was 84% among 25 evaluable patients, including 9 complete responses (36%) and 12 partial responses (48%), said Dr. Andrew W. Roberts, with the Royal Melbourne (Australia) Hospital and Walter and Eliza Hall Institute of Medical Research.

Six of eight complete responders tested were negative for minimal residual disease by flow cytometry.

Preliminary pharmacokinetic results suggest no apparent effect of rituximab on ABT-199 exposure, he said.

Three patients discontinued ABT-199 after achieving a complete remission, including one with fludarabine-refractory disease, and all remain in complete remission at 8.6, 8.8, and 11.6 months after cessation.

Dose modifications were also made in this study following a fatal TLS event in December 2012 after a first dose of ABT-199 at 50 mg. Under the modified step-up dosing, ABT-199 was started at 20 mg, escalating up to 600 mg daily over 5 weeks, with rituximab 375 mg/m² added on day 1 of week 5 and rituximab 500 mg/m² added on day 1 of months 2-6.

The combination was well tolerated, and no new safety concerns were identified, Dr. Roberts said. The most common grade 3/4 adverse events among 45 patients evaluable for safety were neutropenia in 47%, anemia in 16%, thrombocytopenia in 13%, and febrile neutropenia in 7%. Grade 3/4 neutropenia was more common at 600 mg, with the 400-mg dose selected for the ongoing safety expansion cohort. Two serious TLS events occurred, but both were prior to schedule modifications, he said.

One patient in the combination study and 13 in the monotherapy study received treatment for small lymphocytic lymphoma. Response rates and tolerability were similar between CLL and SLL patients in the monotherapy study, Dr. Roberts said in an interview.

During a press briefing at the meeting, Dr. Seymour said ABT-199 potentially could be combined with ibrutinib and that the combination was very potent in laboratory tests in both CLL and some forms of mantle cell lymphoma. Negotiations with the various companies involved are intricate, but there is agreement and commitment "to begin clinical trials of the combination later this year," he added.

ABT-199 is currently being evaluated in a phase II trial as monotherapy in deletion 17p relapsed CLL, as combination therapy with rituximab versus bendamustine plus rituximab in a phase III trial in relapsed/refractory CLL, and in combination trials with bendamustine/rituximab and obinutuzumab in relapsed/refractory CLL.

AbbVie and Genentech sponsored the trials. Dr. Seymour is a consultant and adviser for AbbVie, Genentech, and Roche. Dr. Roberts reported research funding from AbbVie and Genentech and milestone payments to his institution related to ABT-199.

pwendling@frontlinemedcom.com

MILAN – The investigational Bcl-2 inhibitor ABT-199 continues to impress with substantial activity as single-agent or combination therapy in relapsed or refractory chronic lymphocytic leukemia, following dose-scheduling modifications to address the risk of tumor lysis syndrome.

ABT-199 monotherapy

Updated data from all 105 CLL patients in the phase I trial show the overall response rate remains high at 77%, with 23% of patients achieving complete remission.

Seven of 11 complete responders assessed had no detectable minimal residual disease, Dr. John F. Seymour said at the annual congress of the European Hematology Association.

Overall response rates were sustained in the 75%-80% range for high-risk patients with deletion 17p, fludarabine-refractory, or immunoglobulin heavy-chain variable (IGHV)-unmutated CLL; and complete response rates in these subgroups also did not differ from the overall group at 22% to 29%.

Prior results from the first-in-human trial dazzled the leukemia community, but tumor lysis syndrome (TLS) complications, including two fatal events, temporarily halted ABT-199 clinical trials and gave the advantage to its closest competitor, the recently approved and more tolerable CLL drug ibrutinib (Imbruvica).

Use of a modified, ramp-up dosing scheme and aggressive TLS prophylaxis appear to have ameliorated the risk of TLS, with no further clinically significant or grade 3 or 4 events reported in the 49 patients treated with this schema, said Dr. Seymour, director of hematology and cancer medicine at the Peter MacCallum Cancer Centre, East Melbourne, Australia.

Rather than using a 3-week schedule and 50-mg starting dose, the safety expansion cohort received once-daily oral ABT-199 beginning at 20 mg, with weekly adjustments to 50 mg, 100 mg, 200 mg, and 400 mg over 5 weeks.

The 400-mg dose has been identified as the phase II dose, with 59% of patients free of progression at 18 months and beyond on this dose, he said.

As of April 2014, 37 of the 105 patients discontinued treatment, 22 due to progressive disease and 12 for adverse events; in addition, two proceeded to allogeneic hematopoietic cell transplantation, and one needed Coumadin, which is not permitted on protocol.

The median duration of response has not yet been reached for patients treated at doses of 400 mg or above, he said.

The most common treatment-emergent adverse events of any grade were diarrhea (40% of patients), neutropenia (36%), and nausea (35%).

Neutropenia was the only grade 3/4 event occurring in more than 10% of patients (33%), followed by anemia in 10%.

Combination ABT-199

Of substantial interest to many was a second phase Ib study presented in the same session, evaluating the role of ABT-199 with the anti-CD20 antibody rituximab (Rituxan) in relapsed or refractory CLL.

After a median time on study of just 7.5 months, the overall response rate was 84% among 25 evaluable patients, including 9 complete responses (36%) and 12 partial responses (48%), said Dr. Andrew W. Roberts, with the Royal Melbourne (Australia) Hospital and Walter and Eliza Hall Institute of Medical Research.

Six of eight complete responders tested were negative for minimal residual disease by flow cytometry.

Preliminary pharmacokinetic results suggest no apparent effect of rituximab on ABT-199 exposure, he said.

Three patients discontinued ABT-199 after achieving a complete remission, including one with fludarabine-refractory disease, and all remain in complete remission at 8.6, 8.8, and 11.6 months after cessation.

Dose modifications were also made in this study following a fatal TLS event in December 2012 after a first dose of ABT-199 at 50 mg. Under the modified step-up dosing, ABT-199 was started at 20 mg, escalating up to 600 mg daily over 5 weeks, with rituximab 375 mg/m² added on day 1 of week 5 and rituximab 500 mg/m² added on day 1 of months 2-6.

The combination was well tolerated, and no new safety concerns were identified, Dr. Roberts said. The most common grade 3/4 adverse events among 45 patients evaluable for safety were neutropenia in 47%, anemia in 16%, thrombocytopenia in 13%, and febrile neutropenia in 7%. Grade 3/4 neutropenia was more common at 600 mg, with the 400-mg dose selected for the ongoing safety expansion cohort. Two serious TLS events occurred, but both were prior to schedule modifications, he said.

One patient in the combination study and 13 in the monotherapy study received treatment for small lymphocytic lymphoma. Response rates and tolerability were similar between CLL and SLL patients in the monotherapy study, Dr. Roberts said in an interview.

During a press briefing at the meeting, Dr. Seymour said ABT-199 potentially could be combined with ibrutinib and that the combination was very potent in laboratory tests in both CLL and some forms of mantle cell lymphoma. Negotiations with the various companies involved are intricate, but there is agreement and commitment "to begin clinical trials of the combination later this year," he added.

ABT-199 is currently being evaluated in a phase II trial as monotherapy in deletion 17p relapsed CLL, as combination therapy with rituximab versus bendamustine plus rituximab in a phase III trial in relapsed/refractory CLL, and in combination trials with bendamustine/rituximab and obinutuzumab in relapsed/refractory CLL.

AbbVie and Genentech sponsored the trials. Dr. Seymour is a consultant and adviser for AbbVie, Genentech, and Roche. Dr. Roberts reported research funding from AbbVie and Genentech and milestone payments to his institution related to ABT-199.

pwendling@frontlinemedcom.com